Gene clusters containing one or more sets of duplicated genes with related functions are probably the basic genetic functional units. The major histocompatibility systems, such as HLA and H2, are among the most complex gene clusters so far known and studied, and illustrate many of the features of their structure and evolution. They cover about one thousandth of the mammalian genome and include two major sets of cell surface products with different but related functions in the control of immune interactions, as well as genes for complement components and 21-hydroxylase. Molecular analysis has revealed an extraordinary complexity at the genetic level, reflecting a very long and involved evolutionary history. A description of the organization of the HLA system, especially the HLA-D region, and its function and polymorphism forms the basis for considering the evolution of such complex gene clusters.